Unprecedented Stereocontrol in the Synthesis of 1,2,3‐Trisubstituted Tetrahydro‐β‐carbolines through an Asymmetric Pictet–Spengler Reaction towards Sarpagine‐Type Indole Alkaloids

Abstract

The asymmetric Pictet–Spengler (P‐S) reaction of chiral Nb‐ethynyl‐substituted tryptophan methyl ester derivatives (from both d‐ and l‐tryptophan) with a simple aliphatic aldehyde, exhibited unprecedented selectivity towards either of the diastereomeric products. A simple variation of conditions could alter the outcome of the cyclization from either 100 % trans‐selective to 100 % cis‐selective originating entirely from internal asymmetric induction under mild conditions. This resulted in a highly efficient access to both 1,3‐cis‐(1,2,3‐trisubstituted tetrahydro‐β‐carbolines, THβCs) and 1,3‐trans‐(1,2,3‐trisubstituted THβCs). To the best of our knowledge, this type of stereocontrol has never been observed from tryptophan methyl ester derivatives (either D or L) in accessing either 1,3‐disubstituted or 1,2,3‐trisubstituted THβCs. By exploiting this very useful ambidextrous diastereoselectivity, we have set the crucial C‐3 and C‐5 stereocenters of C‐19 methyl‐substituted sarpagine/macroline/ajmaline alkaloids beginning with the DNA‐encoded and cheaper l‐(–)‐tryptophan, as well as optionally from commercially available d‐(+)‐tryptophan.